An Oxygen Self‐Sufficient Nanozyme Engineered From Metal–Organic Cage for Dual‐Modal Self‐Reporting Theranostics

ABSTRACT The development of intelligent theranostic platforms capable of improving tumor‐hypoxic microenvironment and self‐reporting therapeutic status is crucial for overcoming the limitations of conventional photodynamic therapy (PDT). Herein, we report an oxygen self‐sufficient nanozyme by the functionalization of manganese dioxide (MnO 2 ) nanoflowers with supramolecular metal–organic cage (MOC52‐L) photosensitizers for dual‐modal self‐reporting theranostics. This nanozyme integrates catalase‐mimetic activity for oxygen generation with therapeutic enzyme activities, enabling enhanced type I/II combined PDT. The decomposition of MnO 2 component in tumor microenvironment not only efficiently generates oxygen and activates PDT but also specifically triggers the recovery of fluorescence and T1‐weighted magnetic resonance imaging (MRI) signals. The activation of these signals provides real‐time visualization of tumor accumulation and serves as a direct reporter of successful hypoxia alleviation and therapeutic initiation. Moreover, the pockets of MOC52‐L can be employed to capture low‐water‐soluble lificiguat (YC‐1) as effective inhibitors of HIF‐1α for further anti‐angiogenesis and anti‐metastasis. Both in vitro and in vivo studies demonstrated that this nanozyme can non‐invasively visualize the effective treatment zone via signal turn‐on and achieve excellent anti‐tumor performance with high biosafety. This work establishes a generalizable strategy for designing silenced theranostics agents, enabling a single activatable core to enhance imaging‐guided PDT and trigger turn‐on self‐reporting.